Methods and Systems for Delivery of Fluids and Aerosols to Tissue Surfaces, Cavities and Obstructed Passages such as Intranasal Ostia

ABSTRACT

Methods and systems for delivering fluids, aerosols, and/or acoustic energy to target sites on tissue surfaces and within body cavities or lumens, obstructions or undesired materials associated with body cavities and tissue surfaces and, particularly, target sites on tissue surfaces or at obstructions within natural orifices, such as ear, nose and throat passages and, particularly, nasal passages and cavities, are provided. In one aspect, methods and systems for delivering fluids and/or aerosols to target sites such as nasal passages at generally high frequency (e.g., sonic and ultrasound) pulsation rates and at multiple, alternating pulsation rates are provided.

REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation-in-part application of PCTInternational Application No. PCT/US2009/068309 filed Dec. 16, 2009,which claims priority to U.S. provisional patent application Nos.61/138,077, 61/138,083 and 61/138,096, all filed Dec. 16, 2008.

TECHNICAL FIELD

The present invention relates to methods and systems for deliveringfluids, aerosols, and/or acoustic energy to tissue surfaces, bodycavities or lumens, obstructions or undesired materials associated withbody cavities or passageways, or on tissue surfaces. In one aspect, thepresent invention relates to methods and systems for delivering fluidsand/or aerosols to tissue sites at generally high frequency (e.g., sonicand/or ultrasound) pulsation rates. In another aspect, the presentinvention relates to methods and systems for delivering acoustic energy(e.g., sonic and/or ultrasound energy, and including high intensityultrasound (HIU) and high intensity focused ultrasound (HIFU)) directlyto tissue, or to obstructions in passages or cavities such as nasalpassages, sinuses and sinus ostia. In another aspect, methods andsystems of the present invention are employed with catheter systems todeliver fluids, aerosols, and/or acoustic energy to tissue surfaces,body cavities or lumens, obstructions or undesired materials at internalbody sites using minimally invasive interventional catheters.

BACKGROUND

Rhinitis is produced by irritation and inflammation of the mucousmembranes of the nasal cavities and is generally caused by allergicreactions, environmental irritants, bacteria and/or viruses. Symptoms ofrhinitis include runny nose, nasal congestion and post-nasal drip.Rhinitis has been associated not only with discomfort, congestion andnasal conditions, but also sleeping problems, ear conditions andlearning challenges. Treatment generally involves administration ofantihistamines, leukotriene antagonists, nasal corticosteroids,decongestants, allergen immunotherapies, or saline irrigation of sinuscavities.

Sinusitis is produced by a number of pathologic processes, includinginflammation of the sinus cavities, poor mucus transport, obstruction ofpassages from inflammatory debris and growth of biofilms within thesinuses and their drainage systems (ostea). Additionally, resultingstagnation, edema and poor blood flow in the surrounding tissue furtherdecreases the ability of blood borne assistance in the form of immunemodulators and antibiotics to reach the site. Microorganisms encased inbiofilms are notoriously difficult to treat, since the biofilm matrix ishighly resistant both to the action of the immune system and totreatment with antibiotics. Sinusitis therapy may involve salineirrigation and administration of aerosols, as well as the administrationof drugs such as antibiotics, decongestants, antihistamines and nasalsteroids, sinus surgery, balloon sinuplasty and administration ofnebulized antibiotics. Response rates for current therapies aregenerally relatively low, both on a short term and a long term basis.This is likely because of the multifactorial nature of this disease asdescribed above. Each individual therapy used as standard treatment forsinusitis does not address all pathophysiologic causes that accumulateto cause the disease, sinusitis. This is true for other diseases such aschronic ear infections, recurrent skin infections, chronic wounds,vascular plaques, gastroenterologic obstructions and solid tumors.

Nasal irrigators for application of both solutions and aerosols are wellknown and are used to relieve symptoms of sinusitis and rhinitis, suchas nasal congestion. Routine nasal irrigation generally improvessymptoms in adults with chronic rhinosinusitis, as well as children withallergic rhinitis. Irrigating fluid, such as saline, may improve nasalciliary motility and may additionally reduce airway edema and soften themucus, which allows more effective aspiration. Irrigation andaspiration, or suctioning, is typically performed in hospital or medicaloffice environments using installed, wall suction systems that are quitepowerful and can be quite effective. Manual irrigating and/or aspiratingdevices that are available for home use are generally low flow rate, lowaspiration pressure devices. Neti pots and squeeze bottles, for example,are used to irrigate nasal passageways manually and, while theytemporarily relieve symptoms, they provide little long term comfort.

U.S. Patent Publication US 2008/0154183 A1 discloses self-contained,motorized devices that provide continuous or intermittent suction, aswell as continuous or intermittent, on-demand delivery of irrigatingfluid to nasal passages. U.S. Patent Publications US 2009/0281454 A1,2009/0281482 A1, 2009/0281483 A1 and 2009/0281485 A1 disclose additionalfeatures of irrigation and aspiration devices. The disclosures of thesepatent publications are incorporated herein by reference in theirentireties.

Commercial devices provide pulsed mist and/or a pulsating rinse to nasalpassages using misting wands. Recent product improvements include a flextip allowing 360° rotation with a tip locking and release feature,variable, stepless pressure control and a calibrated pulse rate.Different wands may be provided for the pulsed mist and pulsating rinsemodes.

Delivery of liquid rinses and mists to nasal passages is described inthe patent literature. U.S. Patent Publication US 2007/0299396 A1discloses a pulsatile irrigation device producing a calibrated pulsatilerinse of 1200-1250 pulses/min, driven by a piston driven pump assembly.Atomization to droplets of about 15-25 microns is accomplished using abolt encased in the end of the tip. U.S. Pat. Nos. 4,776,990, 4,805,614and WO 2007/129297 disclose devices for home and office use that providewater-saturated, pressurized, heated air to nasal passages.

Many different types of nebulizers and aerosol generators have beendeveloped. Some devices employ ultrasound transducers to nebulizesolutions or generate aerosol droplets. U.S. Pat. No. 3,774,602, forexample, discloses a disposable, cartridge-type single shot ultrasonicnebulizer for inhalation therapy. U.S. Pat. No. 4,109,863 disclosesanother apparatus for ultrasonic nebulization of liquid samples orsuspensions. U.S. Pat. No. 4,319,144 discloses a nebulization controlsystem for a piezoelectric ultrasonic nebulizer. U.S. Pat. No. 6,357,671discloses another ultrasonic nebulizer that is controllable to vary theamplitude of the ultrasonic output.

Liquid aerosols may also be produced using micropumps, includingelectronic micropumps. In one system, a dome-shaped aperture plate ordiaphragm having many tapered holes is vibrated at a high rate (e.g.,100,000 times per second). The rapid vibration causes each aperture toact as a micropump, drawing liquid through the holes and ejectingconsistently sized droplets.

Liquid projection apparatus having addressable nozzles are also known.U.S. Pat. No. 6,394,363 discloses a device having multiple transducersassociated with multiple nozzles for projecting liquid as jets ordroplets from selected nozzles. Related liquid projection apparatus aredescribed in PCT International Publications WO 2008/044069 A1, WO2008/044070 A1, WO 2008/0044071 A1, WO 2008/0044072 A1 and WO2008/0044073 A1.

Application of ultrasound directly or indirectly to the nasal passages,or to tissue in the nasal passages, has also been proposed. Experimentalstudies administering low intensity (1 W/cm²), pulsed (1:9) andcontinuous therapeutic ultrasound at a frequency of 1 MHz to sinuses byapplication of an ultrasound soundhead to the skin of the cheeks andforehead were conducted to ascertain the effect on chronic sinusitis andchronic rhinosinusitis. Ansari et al., Therapeutic ultrasound as atreatment for chronic sinusitis, Physiotherapy Research International,9(3) 144-146 (2004); Ansari et al., Physiotherapy for chronicrhinosinusitis: The use of continuous ultrasound, International Journalof Therapy and Rehabilitation, July 2007, Vol 14, No 7; Ansari et al., Apreliminary study into the effect of low-intensity pulsed ultrasound onchronic maxillary and frontal sinusitis, Physiotherapy Theory andPractice, 23(4):211-218, 2007.

The use of high intensity focused ultrasound (e.g., HIFU) is well knownfor ablation or remodeling of various types of tissue. Ultrasoundcatheter systems for delivering ultrasound energy for ablatingobstructions within blood vessels using an ultrasound transmission wireor ultrasound transmission member are described, for example, in U.S.Pat. Nos. 7,297,131 and 5,989,208.

A handheld, focused ultrasonic therapeutic device for treating skinlesions involved with gynecological disorders is described in U.S.Patent Publication US 2005/0080359. A supersound treatment apparatussuitable for treatment of rhinitis is described in PCT InternationalPatent Publication WO 2008/009186. Devices targeting ultrasound beams onsubepithelial layers of nasal mucosa in the nasal turbinates have beenreported to reduce the volume of inferior turbinates, while increasingthe volume of nasal ventilation.

U.S. Patent Publication US 2008/0027423 discloses a system for treatmentof nasal tissue by application of ultrasound energy directly to tissueregions beneath the surface of the turbinate tissue. Fluid may beinfused or injected directly into the turbinate tissue being treated,e.g. to enlarge the size of the turbinates and ensure delivery ofultrasound energy directly to the tissue. U.S. Patent Publications2007/0244529 and 2008/0027423 relate to injecting fluid into the nasalturbinate using retractable needles at the end of a wand and thendelivering ultrasound energy into the turbinate tissue. The treatment isaccomplished using frequencies of from 0.5 to 12 MHz, generally from 5to 12 MHz. Cooling fluid and/or radio frequency (RF) energy may also bedelivered from the ultrasound and infusion probe.

Other modalities, including surgical techniques, are also used fortreating tissue in intranasal passages. Somnoplasty uses controlled,low-power radiofrequency energy to create one or several submucosalvolumetric lesions, which are resorbed over a period of several weeks toreduce unwanted tissue volume and stiffen remaining tissue in desiredareas. Electrosurgical techniques are used for ablating, shrinking,coagulating or otherwise modifying tissue, including enlarged orhypertrophied nasal turbinates. In some systems, an active electrode ofan electrosurgical probe is positioned in proximity to target tissue inthe presence of an electrically conductive fluid. When a high frequencyvoltage is applied, tissue in proximity to the electrode is ablated,severed, or modified. Endoscopic techniques such as balloon sinuplasty,in which a sinus balloon catheter is positioned across a blocked ostiumand inflated to restructure the blocked ostium, are also used foropening blocked passageways. Placement of stents and other implantabledevices in sinus passageways is also performed to maintain patency.

Rhinitis and sinusitis remain widespread throughout many populationsdespite the many devices and systems described in the prior art.Effective and long-lasting reduction of mucus and accumulatedinflammatory debris and reduction in the growth of biofilms within thenasal passages, sinuses and their drainage systems, remain challengingdespite the proliferation of treatment options. There is a basis forusing both saline and ultrasound individually for the treatment of nasalcongestion, chronic sinusitis and chronic wounds. The disclosurepresented herein is directed, in part, to providing improved methods andsystems for delivery of fluids and aerosols and ultrasound energy totissue surfaces, cavities and obstructed sites in passages, lumens orcavities such as nasal passages, sinuses and sinus ostia.

SUMMARY

There is a basis for using saline and ultrasound, individually, for thetreatment of nasal congestion, chronic sinusitis and chronic wounds. Theapplicants have discovered, unexpectedly, that using saline and otherfluids and aerosols in combination with high frequency acoustic energy,or administering fluids and aerosols by pulsation at high frequencies,such as ultrasound frequencies, provides a synergistic effect. Methodsand systems of the present invention thus, in one aspect, employ theapplication of acoustic energy, such as generally high frequency (e.g.,sonic and/or ultrasound) acoustic energy, directly and/or through thedelivery of pulsed irrigation fluids and/or aerosol flows, to address arange of pathophysiological processes that accumulate, and interact, tocause various illnesses and conditions, and to produce undesiredsymptoms.

Methods and systems of the present invention may be applied for thetreatment of tissue sites such as skin surfaces, organs and internaltissue surfaces, and to obstructions on tissue surfaces or within bodycavities, lumens or the like, for disruption and/or removal of theobstruction(s). The systems may incorporate a guidable insertion wandfor use in connection with external skin surfaces and tissues withinnatural orifices, while a catheter-based system may be used foraccessing desired internal tissue sites. Some embodiments involve thedelivery of acoustic energy directly to tissue or to obstructions, ordelivery of pulsed irrigation fluids and/or aerosol flows, and employmultiple modes of administration, such as delivery of acoustic energyand/or irrigation fluid(s) or aerosol(s) at multiple frequencies (e.g.ultrasound and/or sub-ultrasound frequencies), intensities, pulsedurations, pulse repetition rates, duty cycles, and the like. Yet otherembodiments involve the administration of acoustic energy, or deliveryof pulsed irrigation fluids and/or aerosol flows, according to single ormultiple modes of operation, in combination with another treatmentmodality such as administration of an antimicrobial or therapeuticagent, application of electromagnetic radiation, an electrical field,radio frequency energy, laser energy, microwave energy, or the like.

In one aspect, methods and systems of the present invention produce aliquid stream and/or aerosol particles and/or aerosol droplets anddeliver the liquid and/or aerosol to a tissue surface, or to a cavity orlumen or an obstruction, at generally high frequency pulsations(generally>1500 Hz) in “sonic” (sub-ultrasound) and/or ultrasonicfrequency range(s) and at a generally low pressure. The tissue surfacemay be an external tissue surface, such as a skin surface or a wound, orit may be a tissue surface in a body cavity or lumen, such as in thevascular system, the respiratory system, the gastrointestinal system,the reproductive system, or a natural orifice such as the mouth and/orthroat, the ear, the nose, including the nasal cavity and nasalpassageways. The obstruction may be an obstruction in a body cavity,such as a nasal cavity or passageway or in another natural orifice, orat another internal or external body location and may comprisepathological tissue, cellular debris, or the like. The aerosol maycomprise a suspension of fine solid particles, or liquid droplets, or amixture of solid particles and liquid droplets, and it may be generatedusing a variety of systems known in the art for generating aerosols.

In some embodiments, delivery of an irrigating liquid and/or aerosol maybe accomplished using multiple and/or alternating pulsations havingdifferent frequencies, intensities, pulse durations, pulse repetitionrates and/or duty cycles. Pulsed delivery using generally high frequencypulsations, or alternating pulsations of different frequencies, maypreferentially provide cavity entry (e.g., by Helmholtz principle),biofilm dissolution or reduction, degradation of pathological tissue,acoustic enhancement of delivery of medications or other treatmentmodalities, improvement of circulation, local immune modulation, andother desired effects. Different operating modalities providing deliveryof acoustic energy at multiple frequencies may be provided, and may beselectable by the user, to preferentially promote variousfunctionalities.

Liquid streams and aerosol droplets delivered to tissue surfaces such asskin, natural orifice cavities such as intranasal passages, and toobstructions at a variety of tissue sites by means of generally highfrequency pulsations are preferably aqueous and may consist of saline,or may consist essentially of saline (with small amounts of active orinactive compositions dissolved in or carried by the saline). Liquidstreams and aerosol droplets delivered using high frequency pulsationsmay alternatively, or additionally, comprise saline or another carriersolution comprising antibiotics, antimicrobial agents, drugs, or thelike, dissolved or suspended in the liquid solution and/or delivered asaerosol particles or droplets. Suitable medications for delivery in aliquid stream or as aerosol particles or droplets may comprise (and arenot limited to), in addition to saline, hypertonic saline, lactatedringer's solution, dead sea salt solution, antibiotics, midazolam,fentanyl, insulin, growth hormone, one or more growth factors,gentamycin, clindamycin, ciprofloxacin, cefuroxime, cancer treatmentcompositions such as cancer chemotherapeutic agents, levofloxocin,tobramycin, ampicillin+sulbactam, amphotericin, tobramycin/amphotericincombinations, cefotaxime, ceftriaxone, fluticasone, budesonide,synthetic antimicrobial molecules such as agangiocides, mometasonefuroate monohydrate, xylitol, eucalyptus, tea tree oil, capsaicin,grapefruit seed extract, oil of wintergreen, and the like.

Devices of the present invention for delivery of an irrigating liquidand/or aerosol to a desired site on the skin or within the respiratorysystem or a natural orifice are generally handheld devices comprising ahandle and at least one solution and/or aerosol discharge port. Sourceliquid for discharging onto tissue surfaces, or for generation ofaerosol droplets, may be stored in a reservoir or device assemblyseparate from the handheld device and provided to the handheld deviceusing appropriate tubing, conduits, and the like. Alternatively, devicesof the present invention may incorporate a refillable liquid reservoirfor storing source liquid, or mate with a disposable cartridge or liquidreservoir that may be provided in a pre-filled or fillable format and isattachable to and detachable from the device, generally at the handleportion. Device features and configurations, including irrigation andaspiration features, nozzle features, dual function switch features,articulating head features, pump and fluid control features andaspiration features may be similar to those described in U.S. PatentPublications 2008/0154183 A1, US 2009/0281454 A1, 2009/0281482 A1,2009/0281483 A1 and 2009/0281485 A1, the disclosures of which areincorporated herein by reference in their entireties.

In another aspect, methods and systems of the present invention delivergenerally high frequency (e.g., ultrasound) acoustic energy forapplication directly to tissue surfaces or to obstructions within bodycavities or lumens, including blocked sites or obstructions in orificesor lumens such as in nasal passages. In one embodiment, devices of thepresent invention comprise an insertion wand sized and configured forinsertion into at least a portion of a body cavity or lumen, or forcontacting a target site on a tissue surface or at an obstruction withina body cavity or lumen, and an acoustic energy delivery memberassociated with the insertion wand for conveying generally highfrequency acoustic energy (e.g., ultrasound energy, including highintensity ultrasound (HIU) and high intensity focused ultrasound (HIM))directly to tissues or obstructed sites, such as within nasal passages.

In another embodiment, an acoustic energy deliver member such as anextendable and retractable wire, or another guidable structure, may beprovided for delivering generally high frequency acoustic energy totissue sites. This type of energy delivery member may be positioned inand across cavities, passageways or other body orifices that arepathologically narrowed (e.g., sinus ostia, osteomeatal complexes,vessels and lumens, portions of the gastrointestinal tract, and thelike), providing delivery of energy, such as acoustic energy, to enlargecavities and passageways and restore proper function.

In another embodiment, a deformable expandable member, such as aballoon, may be provided and expanded at a desired site, such as aninternal cavity or passageway, by fluid delivery to the expandablemember. The deformable walls of the expandable member may thus bepositioned in proximity to or in contact with the walls of internalcavities and/or passageways having various configurations. Energy, suchas high frequency acoustic energy, may be delivered through the fluidcontained within the expandable member and through the walls of theexpandable member to the walls of the internal cavities and/orpassageways and neighboring tissues.

Delivery of high frequency acoustic energy provides mechanical andcavitational effects that promote opening of blocked passages andlumens, such as nasal passages, sinuses and sinus ostia. High frequency,generally high intensity acoustic energy may be provided directly to anobstructed site, such as an intranasal passage or another body lumen orcavity, to preferentially disrupt and/or ablate pathological tissue,obstructions, cellular debris and the like, including inflammatorybuildup, bony hypertrophy, various types of plaque, and biofilms.

In some embodiments, delivery of acoustic energy at particularfrequencies, intensities, pulse durations, pulse repetition rates,and/or duty cycles, may be selected to promote effects such as immunemodulation, improved vascularization, bioacoustic effects and improvedefficacy of administered agents such as antibiotic, antimicrobial andother agents. Systems and methods of the present invention may alsoprovide delivery of one or more predetermined sequences of acousticenergy, with each sequence providing delivery of acoustic energy at adifferent frequency, intensity, pulse duration, pulse repetition rate,and/or duty cycle. Multiple sequences may be programmed in the device asmultiple programmed protocols may be selectable by a user. Protocolsdelivering predetermined sequences of acoustic energy may be tailored toand, in some embodiments, may generally match, the array of acousticproperties that a tissue exhibiting a particular pathology and/orinfection may have. In some embodiments, each acoustic energy deliverysequence, or each programmed protocol may target a specific effect,tissue type, administered agent, or the like.

In yet another aspect, methods and systems of the present inventionprovide delivery of an irrigating liquid and/or generally high frequencyacoustic energy (e.g., ultrasound energy) to a desired internal site ofa subject using a catheter assembly. In these embodiments, irrigatingfluid and/or acoustic energy is provided to a tissue site, or anobstruction, at an internal target site, such as a site in the vascularsystem, the respiratory system, the gastrointestinal system, thereproductive system, or the like, using an acoustic energy deliverysystem for delivery of acoustic energy and tubular structures fordelivery of an irrigating liquid. Various systems and methods fordelivery acoustic energy to internal body sites for purposes oftreatment, disruption, ablation and/or removal of undesired tissue orobstructions, and the like, are known in the art and may be used insystems and methods of the present invention. Various types of cathetersemploying ultrasound transducers are disclosed, for example, in U.S.Pat. Nos. 5,362,309, 5,318,014, 5,315,998, 5,269,291, 5,197,946,5,735,811, 5,197,946, 5,989,208, 6,001,069, 6,024,718, 6,623,444,6,855,123 and 7,297,131, the disclosures of which are incorporatedherein by reference in their entireties.

In some embodiments, delivery of an irrigating liquid and/or acousticenergy at particular frequencies, intensities, pulse durations, pulserepetition rates, and/or duty cycles using a catheter-based system, maybe selected to promote effects such as immune modulation, improvedvascularization, bioacoustic effects and efficacy of administered agentssuch as antibiotic, anti-restonosis and other agents. Delivery of one ormore sequences of acoustic energy, with each sequence providing deliveryof acoustic energy at a different frequency, intensity, pulse duration,pulse repetition rate, and/or duty cycle may be provided and multiplesequences may be programmed in a catheter-based system as multipleprogrammed protocols selectable by a user.

Fluid and/or aerosol particles and/or droplets may be supplied inaddition to delivery of high frequency acoustic energy through acousticenergy delivery systems of the present invention, in a continuous orpulsed delivery protocol, to tissue surfaces or to obstructions topromote penetration of blocked sites such as nasal passages, disruptionand opening of undesired blockages, and/or to provide cooling of thetarget site during or following delivery of high frequency (e.g.,ultrasound) acoustic energy. Pulsed delivery using high frequencypulsations promotes entry (e.g., by the Helmholtz principle), biofilmdissolution and acoustic enhancement of medications delivered in theliquid stream and/or aerosol droplets.

Devices of the present invention may incorporate one or more aspirationports for removal of materials from a working site prior to, during orfollowing delivery of fluid and/or aerosol particles/droplets and/orgenerally high frequency acoustic energy. Multiple delivery ports may beprovided for delivery of multiple (different) fluids, or for delivery ofmultiple types of aerosol particles/droplets, sequentially orsimultaneously. Visualization and/or illumination of intranasal targetsites may be provided using optical, acoustic, or other types ofvisualization and illumination systems incorporated in devices of thepresent invention. An endoscopic port may be provided for delivery ofdiagnostic and/or therapeutic tools, agents, and the like. Systems fordelivering additional diagnostic and/or treatment modalities such aselectromagnetic radiation, radio frequency radiation, laser radiation,microwave radiation, and the like, may also be provided in connectionwith methods and systems of the present invention. In one embodiment,systems of the present invention may additionally be adapted fordelivery and placement of implantable devices, such as stents.

Devices of the present invention may also incorporate one or moresystems, such as one or more discrete receptacle(s), for collection ofmaterial removed by aspiration. The collected tissue, obstruction and/ordebris samples may be subjected to various types of diagnostic testing,characterization, and the like. Multiple collection receptacles may beprovided for collection of samples at different stages of a protocol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic illustration showing a handheld device of thepresent invention for delivering fluid and/or aerosol particles ordroplets to a tissue surface or an obstruction, the device being showninserted into a user's nostril and the illustration showing, incross-section, the internal anatomy of the nasal passageways.

FIGS. 2A and 2B show schematic diagrams illustrating the use of a deviceshown in FIG. 1, with FIG. 2A showing insertion of the device into anostril and operation of the device to distribute an irrigating fluidand/or aerosol pulsed at high frequency in the area of clogged nasalpassageways, and FIG. 2B showing subsequent aspiration of the materialfrom the passageways as a result of delivery of the irrigating fluidand/or aerosol.

FIG. 3 shows a schematic drawing illustrating another embodiment of adevice of the present invention for delivering fluid and/or aerosolparticles or droplets and/or acoustic energy (e.g., sonic acousticenergy as well as ultrasound energy) directly to a tissue surface.

FIG. 4 shows a schematic drawing illustrating the device of FIG. 3inserted into a user's nasal passageway to deliver fluid and/or aerosolparticles or droplets and/or acoustic energy (e.g., sonic acousticenergy as well as ultrasound energy) directly to a tissue surface in thenasal passageway and shows, schematically in cross-section, the internalanatomy of the nasal passageways.

FIGS. 5A-5C show schematic drawings illustrating a device similar tothat shown in FIG. 3 for placement and expansion of an expandable member(e.g., balloon) in a body cavity and shows, schematically incross-section, the internal anatomy of the nasal passageways. FIG. 5Ashows an expandable member partially expanded in a nasal and/or sinuscavity; FIG. 5B shows the expandable member nearly fully deployed tocontact the internal surface of a nasal/sinus cavity; and FIG. 5Cschematically shows the application of energy, such as acoustic energy,through fluid in the expandable member and delivery of that energy tosurrounding tissues.

FIG. 6 shows a schematic drawing of another device of the presentinvention inserted into a user's nasal passageway to deliver acousticenergy (e.g., sonic acoustic energy as well as ultrasound energy) to atissue surface in proximity to an opening in an ostea in the nasalpassageway, with or without delivery of fluid and/or aerosol particlesor droplets and shows, schematically in cross-section, the internalanatomy of the nasal passageways.

FIG. 7 shows a schematic drawing of another device of the presentinvention for delivering acoustic energy (e.g., sonic acoustic energy aswell as ultrasound energy) to a tissue surface, with or without deliveryof fluid and/or aerosol particles or droplets.

FIGS. 8A-8E show schematic diagrams illustrating the use of a devicesimilar to that shown in FIGS. 6 and 7, with FIG. 8A showing insertionof the device into a nostril or sinus passage; FIG. 8B showing extensionof an active therapeutic component for delivering generally highfrequency acoustic energy (e.g., ultrasound energy) to a blockage in theosteomeatal complex in the nasal/sinus passageway; FIG. 8C schematicallyshowing delivery of acoustic energy through the active therapeuticcomponent to disrupt the blockage in the osteomeatal complex; and FIG.8D showing aspiration of debris from the site, and FIG. 8E showing theinternal passageways and cavities cleared of debris.

FIGS. 8F-8H show schematic diagrams illustrating the use of a devicesimilar to that shown in FIGS. 6, 7 and 8A-D, modified to deploy a stentin an internal passageway after the passageway has been enlarged orcleared by delivery of acoustic energy delivered, for example, by thesame device. FIG. 8F shows insertion of the device and initialdeployment of the stent over a guide; FIG. 8G shows further deploymentof the stent along the guide in the osteomeatal complex; and FIG. 8Hshows final positioning of the stent in the osteomeatal complex.

FIGS. 9A-9D show schematic diagrams illustrating the use of a devicesimilar to that shown in FIGS. 6, 7 8A-D, modified to deploy anexpandable member, such as a balloon, over a guide member. FIG. 9A showsinsertion of the device and initial deployment of the expandable memberover the proximal portion of the guide; FIG. 9B shows further deploymentof the expandable member along the guide; FIG. 9C illustrates oneembodiment of an expandable member fully deployed over a guide tointimately contact internal passageways and cavities; and FIG. 9Dschematically shows the application of energy, such as acoustic energy,through fluid contained in the expandable member and delivery of thatenergy to surrounding tissues.

FIGS. 10A-10C show highly schematic diagrams illustrating interventionalcatheter-based systems of the present invention for accessing internaltissue sites, such as blood vessels, air passageways, thegastrointestinal and genitourinary tracts, and the like, which are notconveniently accessible through a natural orifice. FIG. 10A shows aschematic diagram illustrating a control device, a catheter and anenlarged view of a distal operating head having properties similar tothe device shown in FIG. 3; FIG. 10B shows a schematic diagramillustrating a control device, a catheter and an enlarged view of adistal operating head having properties similar to the device shown inFIGS. 5A-5C; and FIG. 10C shows a schematic diagram illustrating acontrol device, a catheter and an enlarged view of a distal operatinghead having properties similar to the device shown in FIGS. 7, 8A-8D,8F-8H and 9A-9D.

Like numbers have been used to designate like parts throughout theseveral drawings to provide a clear understanding of the relationship ofthe various components and features, even though different views areshown. It will be understood that the appended drawings are notnecessarily to scale, and that they present a simplified, schematic viewof many aspects of systems and components of the present invention.Specific design features, including dimensions, orientations, locationsand configurations of various illustrated components may be modified,for example, for use in various intended applications and environments.

DETAILED DESCRIPTION

Specific methods and systems of the present invention for pulseddelivery of liquids and/or aerosols, and/or for delivery of generallyhigh frequency, generally high intensity acoustic energy (e.g.,ultrasound) to intranasal areas such as nasal passages, sinuses andsinus ostia, are described with reference to the accompanying drawings.It will be appreciated that these specific embodiments are illustrative,and that systems and methods of the present invention may be used in avariety of applications, as described elsewhere in this specification.

FIG. 1 shows a schematic illustration of one embodiment of device forpulsed delivery of liquids and/or aerosols to a subject's nasalpassages. As shown in FIG. 1, device 10 comprises a handle 12, a nostrilinterface member 14 and a discharge port 16. Handle 12 has a size andconfiguration that facilitates holding in one or both hands and mayinclude ridges, indentations, curved contours, and the like, to enhancethe ergonomic feel and secure handling of the device. Handle 12 mayinclude at least one activation mechanism, such as control 15, foractivating one or more device functions. In one embodiment, for example,control 15 may be operated by a user to activate, or inactivate, apulsatile flow of liquid and/or aerosol from discharge port 16 innostril interface member 14.

Handle 12 may also house power supply and control elements for operatingthe device. Power may be supplied to device 10 by physical connection toan electrical power source such as a separate control unit or anelectrical outlet by means of a conventional power cord, as is wellknown in the art. Power may alternatively be supplied by a batterysource mounted in the handle. Battery power sources may be provided asreplaceable or rechargeable components. Battery charging may beaccomplished by direct coupling of battery terminals, or conductiveelements provided on the housing, with a power source, or by indirectcoupling using, for example, an inductive charging system. Handle 12 mayalso house control mechanisms, such as mechanical or electronicswitches, microprocessors, power supplies, and the like, and may housean aerosol generation device and/or the system for generating pulsatiledischarge of liquid and or aerosol droplets.

Handle 12 and nostril interface member 14 may be provided in anintegrated, single piece construction, or they may be provided asseparate components that are detachable from one another. Nostrilinterface member 14 comprises at least one discharge port 16 at a distalend of the member, and generally has a size and configuration thatpermits insertion of a distal end of the interface member and dischargeport 16 into the nostril of a user. The distal end of the nostrilinterface member may have a generally curved or tapered configuration,with a smaller diameter area at the discharge outlet, such that thedischarge outlet and distal end of the interface member may be insertedinto the nostril, while more proximal surfaces of the nostril interfacemember contact the nostril opening and effectively “seal” the openingduring use of the device. In some embodiments, the nostril interfacemember may be flexible and may comprise a telescoping structure thatpermits extension and retraction of the member, or adjustment of themember to different sizes or configurations. In some embodiments, thenostril interface member may be articulatable with respect to thehandle.

In one embodiment, devices of the present invention are capable ofdelivering a liquid stream in a generally high frequency pulsatile flow.In another embodiment, devices of the present invention are capable ofgenerating aerosol particles and/or droplets, and delivering the aerosolparticles and/or droplets in a generally high frequency pulsatile flow.In yet another embodiment, devices of the present invention are capableof selectively delivering a liquid stream, aerosol particles and/oraerosol droplets, simultaneously or sequentially, in a generally highfrequency pulsatile flow. Liquid, aerosol particles and/or aerosoldroplets may be delivered from a common discharge port sequentially andintermittently, or from multiple, dedicated discharge ports,simultaneously or sequentially, and on a continuous or intermittentbasis.

An aspiration channel may optionally be provided for removal of materialloosened by the application of pulsed liquid and/or aerosol flows from asite, such as nasal passageways. Aspiration may be provided through acommon port as fluid and/or aerosol delivery, or through an additionalaspiration port provided in the nostril interface member 14, or throughan aspiration port provided in an auxiliary device. Although anaspiration system employing a vacuum device may be provided integrallywith the device and an aspiration reservoir may be incorporated into thedevice or used in connection with the device, aspiration may also beaccomplished by interfacing an aspiration channel within the device witha vacuum or suction source provided in a medical facility. Interfacetubing may be provided for this purpose.

FIGS. 2A and 2B show, schematically, operation of a device asillustrated in FIG. 1. Nostril interface member 14 is inserted into andgenerally contacted to a user's nostril. For some applications, thenostril interface member may be sized and configured to form asubstantially liquid-tight seal against a user's nostril when insertedand upon continued application of pressure in the insertion direction.After insertion and placement of the nostril interface member, the useractivates a desired delivery protocol for delivery of a liquid stream,aerosol particles and/or aerosol droplets, simultaneously orsequentially, in a generally high frequency pulsatile flow, throughdischarge port 16. This is shown schematically by the curved dashedlines. The pulsatile delivery of liquids and/or aerosols facilitatespenetration of fluids and particles through passageways and blockagesand may also deliver a therapeutic effect to tissue surfaces. Liquidsand other material, including debris, mucus, infected tissue, and thelike may be withdrawn by aspiration using the same device followingpulsatile delivery of liquids and/or aerosols, as shown schematically inFIG. 2B.

Controls may be provided on the device handle, illustrated as actuator15, or on an accessory device or module, allowing a user to selectliquid and/or aerosol delivery modes, or allowing a user to select amongvarious modes of operation or various pre-determined operating programs.In one embodiment, for example, a device such as that illustrated inFIG. 1 may be operated in an aerosol delivery mode whereby, uponactivation, aerosol particles and/or droplets are pulsated anddischarged from outlet port 16 at a generally low pressure and highfrequency. In another embodiment, a single mode device may be operatedin a liquid delivery mode whereby, upon activation, a high frequencypulsating liquid stream is discharged from outlet port 16, continuouslyor intermittently. In yet another embodiment, a user may selectpulsating liquid and/or aerosol discharge modes which may also operateon a continuous or intermittent basis.

In some embodiments, multiple pulsating irrigation fluid and/or aerosoldelivery options may be programmed in the device, with various operatingprograms being predetermined and, optionally, selectable by the user. Inone embodiment, for example, a control may be actuated by a user toinitiate a predetermined or selectable cycle involving multipleirrigation fluid and/or aerosol delivery protocols. Multiple differentdelivery protocols may involve delivery of irrigation fluid and/oraerosol at pulsation rates having a selected frequency, intensity, pulseduration, pulse repetition rate, duty cycle, and the like. Multipledifferent delivery protocols may additionally involve delivery ofdifferent types (e.g., composition, concentration, osmolarity, and thelike) of irrigation fluids, and/or different types (e.g., composition,concentration, particle size, and the like) of aerosols.

In one embodiment, for example, a therapeutic cycle may provide deliveryof from one to several different pulsation cycles that correlate withthe acoustic properties of each contributing pathologic process thatcontributes to the disease or symptomology (e.g., sinusitis, earinfection, pneumonia, chronic skin wounds, gastroenterologic processes,tumors, and the like.) Pathologic processes that may be targeted by thetherapeutic cycle may include (but are not limited to) biofilms,inflammation, mechanical obstruction, hypertrophy, poor circulation,lithiases (stones/calcifications), dysfunctional immuneresponse/modulation, and the like. In alternative embodiments, a usermay select pulsating liquid rinse and/or aerosol delivery options bymeans of multiple selectable actuators. In any of these embodiments,multiple and selectable modes may be implemented, whereby programmed orselectable levels of liquid and/or aerosol flow or volume, aerosolparticle and/or droplet size, aerosol particle and/or droplet density,pulsation frequency, temperature, and the like, may be selectable by theuser.

In one embodiment, for example, different pulsation characteristics maybe provided to promote different effects. Optimal pulsation frequenciesfor promoting sinus entry (resonance), biofilm dissolution, dragenhancement, immunomodulation and circulatory regulation may bedifferent; user selectable controls may be provided for selectingpulsation frequencies or modes of operation to promote each of thesefunctions. Alternatively, one or more pre-programmed timing sequences ofapplication of multiple frequencies may be provided.

Aerosol generation may be accomplished using aerosol generators, such aspumps, aperture plates or diaphragms, ultrasound transducers (e.g.,piezoelectric crystals), and other systems that are well known in theart. In one embodiment, solution provided at a generally low pressure isconveyed through a standard jet nebulizer to produce aerosol or finelydivided liquid droplets. Aerosol droplets generated and discharged bydevices of the present invention preferably have a droplet size of fromabout 0.5μ to about 200μ, in some embodiments from about 1μ to about100μ, in other embodiments from about 3μ to about 60μ, and in yet otherembodiments from about 5μ to about 30μ, entrained in gas (e.g. air).

Pulsation of the liquid and/or aerosol particles and/or droplets isgenerally accomplished at a frequency in excess of 100 Hz and may beaccomplished at an ultrasound frequency of 20 kHz or higher. Devices ofthe present invention may provide either or both ultrasonic andsub-ultrasonic (sonic) oscillation of a liquid stream or aerosol as itexits the discharge outlet. A liquid flow may be pulsated at onefrequency, such as a frequency less than 10 kHz, while aerosol dropletsmay be pulsated at a different frequency, generally at a higherfrequency. Aerosol may be pulsated at frequencies in excess of about1500 Hz, and in some embodiments in excess of about 5000 Hz, andgenerally at frequencies less than 10 MHz. In some embodiments, aerosolis pulsated at frequencies in excess of about 10 kHz, from about 10 kHzto about 100 kHz, in some embodiments from about 15 kHz to about 50 kHz,and in yet other embodiments from about 20 kHz to about 40 kHz.

Aerosol particles or droplets may alternatively be pulsated at two ormore alternating frequencies. In one embodiment, aerosol may be pulsatedat multiple alternating, sub-ultrasonic frequencies. In anotherembodiment, aerosol is pulsated at two or more alternating frequencies,with one or both of the frequencies being an ultrasonic frequency.According to one embodiment, for example, aerosol delivery is providedby pulsation at multiple frequencies, such as at an ultrasonic frequencyof from about 20 kHz to about 40 MHz and at one or more additionalultrasonic or sub-ultrasonic frequencies.

The pulsation frequency of delivery of liquid and/or aerosol streams maybe alternated by providing multiple pulsation generators, or byoperating a single pulsation generator at different frequencies and/orenergies. Various cycles may be implemented and, in some embodiments, auser may selectively control aerosol generation and pulsation, while inother embodiments, predetermined cycles of aerosol generation andpulsation may be provided. In one embodiment, for example, a column ofmist is generated in the space between the transducer and an aerosoldischarge orifice when the transducer is operated at the aerosolgeneration frequency, and the column of mist is then pulsated as itexits the discharge orifice when the device is operated at the pulsationfrequency. Cycles may be established, and predetermined, to operate thetransducer in an aerosol generation mode for a time sufficient togenerate a suitable aerosol column, and then to operate the transducerin the pulsation mode for a time sufficient to discharge the aerosolfrom the column.

According to some embodiments, a single piezoelectric crystal or anotherultrasound generating device may be operated in different modes,sequentially, to produce both aerosol and high frequency pulsations ofliquid and/or aerosol. In another embodiment, multiple ultrasoundtransducers (e.g., two piezoelectric crystals) may be operated inaerosol generation and pulsation modes, respectively, simultaneously orintermittently, to generate aerosol and then to pulsate the generatedaerosol at a generally high frequency. A dedicated aerosol generationtransducer may be operable, for example, in a single operating conditionor in multiple operating conditions, and a dedicated pulsationtransducer may, similarly, be operable at a single pulsation frequency,or at multiple selectable pulsation frequencies.

In one embodiment, an aerosol generation system (e.g., a piezoelectriccrystal or ultrasound transducer) and an aerosol pulsation system (e.g.,an ultrasound transducer) are located separately. An aerosol generationtransducer may be located at a liquid solution interface, for example,to generate a column of aerosol droplets extending above the liquidsolution interface. An aerosol pulsation system, such as an ultrasoundtransducer, may be located along an aerosol column or in proximity to anaerosol discharge orifice, providing pulsatile discharge of aerosol froma discharge port.

In another embodiment wherein ultrasound transducers are used both foraerosol generation and pulsation, an aerosol generation transducer andan aerosol pulsation transducer may be located in proximity to oneanother. Multiple transducers may be collocated, for example, with anaerosol generation transducer provided in a central position, and apulsation transducer provided as an annular transducer positioned aroundthe central aerosol generation transducer to provide pulsation of theaerosol at discharge. Multiple transducers may be operatedsimultaneously to both generate and pulsate aerosol simultaneously.Alternately, an aerosol generator may be operated to generate a columnof aerosol and the aerosol pulsation transducer may be operatedindependently to pulsate the generated aerosol. The aerosol generationtransducer may be immersed in liquid and in direct contact with theliquid, or it may be in indirect contact with liquid through a flexiblemembrane or diaphragm.

Devices of the present invention may additionally incorporate a heater,or a thermostat for controlling the temperature of liquid discharged ina liquid stream, of for controlling the temperature aerosol at or priorto discharge. A heating element may be provided, for example, inproximity to a wall defining the mist column to heat the mist as itmoves through the column to a temperature of from about 30-50° C., insome embodiments from about 35-45° C., and in yet other embodiments fromabout 38-43° C. In some embodiments, the aerosol is heated to atemperature above the average human body temperature (37° C.) prior todischarge from the device.

FIGS. 3-5 show schematic illustrations of devices of the presentinvention for delivery of generally high frequency acoustic energy(e.g., sonic and/or ultrasound energy, including high intensityultrasound (HIU) and high intensity focused ultrasound (HIFU)) to tissuesites such as nasal passages. As shown in FIG. 3, device 20 comprises ahandle 22, an insertion wand 24 and an acoustic energy delivery member26. In devices intended for delivery of high frequency (sonic andultrasound) acoustic energy directly to internal sites, such as nasaland sinus passageways, insertion wand 24 is configured for insertionthrough a nostril opening and positioning at least partially withinnasal passageways. Insertion wand 24 is generally cylindrical and may beconstructed as a flexible, catheter-like structure having at least onelongitudinally oriented lumen extending therethrough. External surfacesof the insertion wand may be provided with a surface texture, orcoating, such as a hydrophilic or hydrophobic coating, to ease passageof the insertion wand though nasal passages and improve deliverability.External surfaces of the insertion wand may also be provided withantibacterial coatings or coatings through which drugs or other agentsare provided.

Insertion wand 24 may incorporate multiple lumens, channels or the likethat communicate with source liquids, aerosol particles and/or droplets,vacuum sources, liquid and/or vacuum manifolds, or the like, to providedelivery of liquids, aerosol particles and/or droplets, vacuum, or thelike, to intranasal passages. Multiple lumens may be co-axial withrespect to one another, or they may be aligned on different axes and benon-concentric with respect to one another. In these embodiments,insertion wand 24 is generally provided with one or more discharge ports25 in proximity to a distal area, providing intranasal delivery of aliquid and/or aerosol particles and/or droplets. Insertion wand 24 may,alternatively or additionally, be provided with one or more aspirationports 27 in proximity to a distal area, providing withdrawal ofdelivered liquids and degraded materials from an intranasal site when anaspiration system (e.g. vacuum) is activated. A distal end of insertionwand 24 may additionally incorporate an endoscopic port and/orcomponents of a visualization system, such as an optical or ultrasoundguidance and/or visualization system.

Energy delivery member 26 may be provided at the tip of the insertionwand and configured for positioning in proximity to and/or contactingblockages within nasal passages, mucous membranes and nasal turbinates,or pathological or undesired tissue. In one embodiment, energy deliverymember 26 may comprise a tapered structure, such as a generally conicalstructure, for focusing and concentrating high frequency and/or highintensity acoustic energy. Conical structures for delivering highintensity focused ultrasound are described, for example, in U.S. Pat.Nos. 6,666,835, 6,500,133 and 6,217,530. An energy delivery member orsurface may be extendible and/or retractable with respect to handle 22and/or insertion wand 24 to provide desired positioning of the energydelivery member in contact with obstructions and/or tissues for deliveryof high frequency acoustic energy. In some embodiments, the energydelivery member, and/or distal portions of the insertion wand, may beconstructed of a light transmitting material, and the device may beadapted to delivery light energy, such as but not limited to ultravioletlight energy, to a desired through the energy delivery member and/or theinsertion wand.

In another embodiment, as illustrated in FIGS. 5A-5C, an energy deliverymember may comprise a flexible, deformable bladder or inflatable chamber28 adapted for retaining an acoustically transmissive material, such asa liquid or gel, within its interior volume. The chamber is controllablyexpandable to contact tissue surfaces in oddly shaped and unevenlycontoured cavities, providing delivery of acoustic energy, through theacoustically transmissive material contained within the interior volume,to tissue surfaces contacting and in close proximity to the chamber.Delivery of acoustic energy, such as ultrasound energy, to tissuesforming the walls of cavity and passageway lumens is otherwisedifficult.

The flexible, deformable chamber may be stored in a collapsed conditionwithin wand 24, for example, and expanded, or inflated, at the desiredtarget site from a distal tip of the wand by filling with anacoustically transmissive material. Expandable chamber 28 may beenlarged at a desired target site, as shown schematically in FIGS.5A-5C, until the walls of the chamber contact a tissue site, such as thewalls of a cavity or passageway or lumen. The chamber walls may beexpanded to contact, or be positioned in close proximity to, walls ofirregularly shaped cavities and passageways for delivery of energy tothe tissue. Energy, such as generally high frequency acoustic energy,e.g. ultrasound to energy, may be applied to the tissue surfaces orobstructions in contact with the chamber wall by transmission of theacoustic energy through the acoustically transmissive material and thewall of the inflatable chamber to deliver acoustic energy directly tothe tissue contacting or in close proximity to the wall of chamber wall,and to neighboring tissues as shown schematically in FIG. 5C. Thisembodiment provides effective delivery of ultrasound energy to tissuesurfaces, cavities and obstructions over a larger surface area thanpoint contact and provides effective access to target sites that mayotherwise be difficult to access with an ultrasound applicator.

The bladder or inflatable member(s) may be constructed from a materialthat has generally high acoustic transmissivity properties and that,when filled with an acoustically transmissive material, provides aflexible surface that is expandable and deformable to conform tocontours of internal cavities or passageways, such as intranasalpassages. The inflatable member may be coated with a drug or anotheragent, particularly an agent whose activity is enhanced in the presenceof high frequency acoustic energy, such as ultrasound energy.

An expandable chamber may also be employed for delivery of a compositionsuch as a drug or another agent, to internal body cavities andpassageways. The inflatable member may, for example, be permeable orporous over at least a portion of its surface to deliver a drug oranother agent to a target site. In one embodiment in which the system isused to delivery high frequency acoustic energy to a desired targetsite, the inflatable member may be expanded using a substance comprisingboth an acoustically transmissive material and one or more bioactivecompositions. The bioactive composition(s) may be eluted or otherwisereleased from the expandable member prior to or during delivery ofacoustic energy through the expandable member. This embodiment may beemployed, for example, for delivery of an agent whose activity isenhanced in the present of high frequency acoustic energy, such asultrasound, to the target site.

A distal end of the energy delivery member is preferably navigable todesired treatment sites, such as tissue surfaces and obstructions, suchas blocked sites within nasal passages, where it can be activated toprovide mechanical and cavitational effects that promote recanalizationof obstructed passages. The energy delivery member may have a pre-formedshape or it may be flexible or conformable, as described above. Energydelivery members having different pre-formed shapes may also be used. Aproximal end of energy delivery member 26 is connected or connectable toa generally high frequency acoustic energy generator (e.g., anultrasound transducer) or acoustic energy coupling, providing deliveryof high frequency acoustic energy (e.g., ultrasound) to the energydelivery member.

High frequency acoustic energy delivered through energy delivery member26, or through an energy delivery member incorporating an expandablechamber, generally has a frequency of greater than about 20 kHz and lessthan about 25 MHz; in some embodiments from about 20 kHz to about 100kHz; in some embodiments from about 20 kHz to about 50 kHz; in otherembodiments greater than about 100 kHz and less than about 1 MHz; inother embodiments from about 500 kHz to about 15 MHz; and in yet otherembodiments greater than about 500 kHz and less than about 5 MHz. Theacoustic energy applied through the energy delivery member may be at agenerally high intensity of from about 1 mW/cm² to about 5 W/cm²; insome embodiments from about 50 mW/cm² to about 3 W/cm²; in otherembodiments from about 5-100 mW/cm²; in yet other embodiments from about0.1-1.5 W/cm². In other embodiments, the acoustic energy applied throughthe energy delivery member may be a generally high intensity ultrasoundof greater than about 1 W/cm² and less than about 25 kW/ cm². In someembodiments, the acoustic energy applied through energy delivery memberhas an acoustic intensity from about 10 to about 1,000 W/cm²; in someembodiments from about 1,000 to about 15,000 W/cm²; and in yet otherembodiments from about 3,000 to about 10,000 W/cm². The generally highintensity ultrasound may be sufficient to ablate tissue and/or cellularstructures or debris, or it may be at a sub-ablation intensity that issufficient to disrupt tissue and/or cellular structures or debris butnot ablate. The pulse duration and repetition rate may be adjusted andmatched to the frequency and intensity of acoustic energy pulses toachieve the desired effect.

The high frequency acoustic energy may be selectably activated on acontinuous basis, or ultrasound energy may be applied, through theenergy delivery member, on an intermittent basis, and the frequencyand/or acoustic intensity may be adjustable and selectable by theoperator. Operation of the ultrasound transducer at duty cycles of lessthan about 80% is generally preferred; in some embodiments at dutycycles of less than 50%; and in yet other embodiments at duty cycles ofless than about 30%. Enhancement and/or coupling agents promoting and/ortargeting acoustic energy deposition may be used and may be provided toa target site through the insertion wand and/or the energy deliverymember.

Handle 22 has a size and configuration that facilitates holding in oneor both hands and may include ridges, indentations, curved contours, andthe like, to enhance the ergonomic feel and secure handling of thedevice. Handle 22 may house power supply and control elements foroperating the device. Power may be supplied to device 20 by physicalconnection to an electrical power source such as a separate control unitor an electrical outlet by means of a conventional power cord, as iswell known in the art. Power may alternatively be supplied by a batterysource mounted in the handle. Battery sources may be replaceable orrechargeable. Battery charging may be accomplished by direct coupling ofbattery terminals, or conductive elements provided on the housing, witha power source, or by indirect coupling using, for example, an inductivecharging system. Handle 22 may also house control mechanisms, such asmechanical knobs 21A, 21B and 21C, or electronic switches,microprocessors, power supplies, and the like. Knobs 21A, 21B and 21Cmay provide user operable control of irrigation fluid, aerosol delivery,delivery of generally high frequency acoustic energy, selection ofmultiple modes of operation and/or multiple programmed protocolsequences, aspiration, other operating modalities, and the like.

Liquids and/or aerosols may be delivered through the insertion wand 24and ports positioned along or generally at a distal end of the insertionwand, similarly to the delivery of liquids and/or aerosols describedwith reference to the device illustrated in FIGS. 1, 2A and 2B.Aspiration may also be provided in devices such as those illustrated inFIGS. 3-5, that deliver generally high frequency acoustic energy, suchas ultrasound energy. Aspiration may be provided through one or moreports positioned along or generally at a distal end of the insertionwand, similarly to the aspiration feature described with reference tothe device illustrated in FIGS. 1, 2A and 2B.

Handle 22, insertion wand 24 and energy delivery member 26 may beprovided in an integrated, single piece construction, or they may beprovided as separate components that are detachable from one another.Handle 22 may be provided as a single- or multiple-use component.Insertion wands and/or energy delivery members may similarly be providedas integrated components or may be provided separately from one another,with appropriate interfaces for operation. Multiple configurations ofinsertion wands and/or energy delivery members may be provided foroperation on common or multiple handles, with appropriate insertionwands and/or energy delivery members being selectable by a userdepending on the circumstances of use. Insertion and energy deliverymembers may be provided as single- or multiple-use components, althoughthey may generally be provided as sterile, disposable components thatare mountable on a reusable handle. Device 20 may incorporate all of thecomponents required for operation, or it may interface with a separateconsole, or control unit (not shown), that provides electrical power,liquid for infusion or aerosol delivery, operating control features,displays, and the like.

In some embodiments, devices of the present invention are capable ofselectively delivering high frequency acoustic energy, a liquid stream,aerosol particles and/or aerosol droplets, simultaneously orsequentially, in one or a plurality of delivery modes: continuous flow;intermittent flow; or high frequency pulsatile flow. Liquid, aerosolparticles and/or aerosol droplets may be delivered from a commondischarge port sequentially and intermittently, or from multiple,dedicated discharge ports, simultaneously or sequentially, and on acontinuous or intermittent basis. Aspiration may be provided,additionally or alternatively, through one or more ports in theinsertion wand and/or energy delivery member. Insertion wand 24 may beprovided with one or more channels, or lumens, for delivery of liquids,aerosol particles, and/or aerosol droplets to a desired intranasal site,and for removal of material from the site by means of aspiration.

Controls may be provided on the device handle, as illustrated, or on anaccessory device or module, allowing a user to select acoustic frequencyand/or intensity, liquid and/or aerosol delivery modes, aspirationmodes, visualization modalities, or the like. Controls may also beprovided allowing a user to select from among various modes of operationor various pre-determined or pre-set operating modes. Devices of thepresent invention may thus be operated, manually or by selectableautomated operation, in a single mode or multiple modes.

In one embodiment, for example, a device such as illustrated in FIGS.3-5 may be operated in a high frequency acoustic energy deposition modein which the insertion wand and energy delivery member are positioned ina nasal cavity, with the energy delivery member contacting mucus and/ordebris forming an obstruction, or tissue desired to be treated. Acousticenergy delivery may be activated at a preset or selectable acousticenergy frequency and/or intensity to heat and/or cavitate and/or ablatemucus and/or debris forming the obstruction. In another embodiment, theenergy delivery member may be positioned to contact tissue and activatedat preset or selectable acoustic energy frequency and/or intensitylevels to heat and/or cavitate and/or ablate selected tissue sites.Delivery of the high frequency and/or high intensity acoustic energy maybe accompanied by infusion of liquids and/or aerosol particles ordroplets, and/or by aspiration or liquids, wastes, mucus, and the like,from the site of energy deposition.

In some embodiments, multiple pulsating liquid rinse and aerosoldelivery options, as well as multiple energy deposition options, may beprogrammed in the device, with various operating programs beingpredetermined and selectable by the user. In alternative embodiments, auser may select pulsating liquid rinse, aerosol delivery and/or energydeposition options by means of multiple selectable actuators. In any ofthese embodiments, multiple and selectable modes may be implemented,whereby programmed or selectable levels of liquid and/or aerosol flow orvolume, aerosol particle and/or droplet size, aerosol particle and/ordroplet density, pulsation frequency, temperature, acoustic energyfrequency, intensity, pulse repetition rate, duty cycle, and the like,may be selectable by the user.

FIGS. 6 and 7 show schematic illustrations of two embodiments of adevice for delivery of generally high frequency acoustic energy to nasalpassages. As shown in FIG. 6, device 40 comprises a handle 42, aninsertion member 44 and an acoustic energy delivery member 46. Insertionmember 44 is configured for insertion through a nostril opening andpositioning at least partially within nasal passageways, for example atan opening to an ostea, as shown schematically in FIG. 6. Insertionmember 44 is generally cylindrical and may be constructed as a flexible,catheter-like structure having at least one longitudinally orientedlumen extending therethrough. External surfaces of the insertion membermay be provided with a surface texture, or coating, such as ahydrophilic or hydrophobic coating, to ease passage of the insertionmember though nasal passages and improve deliverability. Externalsurfaces of the insertion member may also be provided with antibacterialcoatings or coatings through which drugs or other agents are provided.The coatings may also provide the elution of active compounds from thesurfaces during the procedure.

Insertion member 44 may incorporate multiple lumens, channels or thelike that communicate with source liquids, aerosol particles and/ordroplets, vacuum sources, liquid and/or vacuum manifolds, or the like toprovide delivery of liquids, aerosol particles and/or droplets, vacuum,or the like, to intranasal passages. Multiple lumens may be co-axialwith respect to one another, or they may be aligned on different axesand be non-concentric with respect to one another. In these embodiments,insertion member 44 is generally provided with one or more dischargeports 45 in proximity to a distal area, providing intranasal delivery ofa liquid and/or aerosol particles and/or droplets. Insertion member 44may, alternatively or additionally, be provided with one or moreaspiration ports 47 in proximity to a distal area, providing withdrawalof material from an intranasal site when an aspiration system (e.g.vacuum) is activated. A distal end of insertion member 44 mayadditionally incorporate components of a visualization system, such asan optical or ultrasound guidance and/or visualization system.

Energy delivery member 46 is generally provided as a structure having asmaller diameter cross-section that that of insertion member 44,providing access to smaller passages or allowing penetration ofobstructions. Energy delivery member 46 is configured such that a distalend may be positioned in proximity to and/or contacting tissue surfacessuch as mucous membranes and nasal turbinates or polyps, bonyprotuberances, undesired tissue growths or accumulations or blockageswithin cavities such as nasal passages. In one embodiment, illustratedin FIG. 6, energy delivery member 46 comprises a generally rigid orsemi-rigid wire-like structure capable of conveying, and delivering,high frequency acoustic energy (e.g., ultrasound energy, including highintensity ultrasound (HIU) and high energy focused ultrasound (HIFU)) bycontact with tissue or obstructive material along its length and/or at adistal end of the delivery member. In another embodiment, illustrated inFIG. 7, the energy delivery member may comprise a flexible, steerablestructure 48. The energy delivery member may be extendible and/orretractable with respect to handle 42 and/or insertion member 44 toprovide desired positioning of the energy delivery member in contactwith obstructions and/or tissues for delivery of high frequency acousticenergy.

A distal end of the energy delivery member 46, 48 is preferablynavigable to target tissue sites or target blocked sites withincavities, such as nasal passages and blocked ostea, where it can beactivated to provide mechanical and cavitational effects that promoterecanalization of obstructed passages. The energy delivery member 46, 48may be extendible and retractable with respect to the insertion member44, as shown in the simplified operational sequence schematicallyillustrated in FIGS. 8A and 8B. Energy delivery member 46 is generallyconstructed from an acoustically transmissive material and may havedifferent stiffness properties along its length, providing steerability.The energy delivery member may have a pre-formed shape, illustrated asan angled shape as shown in FIG. 6, or may be flexible or conformable,as illustrated schematically in FIG. 7. Energy delivery members havingdifferent pre-formed shapes may also be used. The energy delivery membermay be constructed from metallic materials, such as Nitinol. Wire-likeenergy delivery members may be covered with another acousticallytransmissive material, such as a resilient rubber-like material, thatmay function to delivery high frequency acoustic energy uniformly or ina focused fashion.

A proximal end of energy delivery member 46, 48 is connected orconnectable to a generally high frequency acoustic energy generator(e.g., an ultrasound transducer) or acoustic energy coupling, providingdelivery of high frequency acoustic energy (e.g., ultrasound) along thelength of and to a distal end of the energy delivery member 46, 48. Insome embodiments, a guidance member, such as a guidewire-type member,may be provided and operated separately from an energy delivery member.In this embodiment, the guidance member may be advanced and positionedat a desired operating site, and the energy delivery member may then beadvanced over along-side or through the guidance member for positioningand activation at the desired operating site.

High frequency acoustic energy delivered through energy delivery members46, 48 generally has a frequency of greater than about 20 kHz and lessthan about 25 MHz; in some embodiments from about 20 kHz to about 100kHz; in some embodiments from about 20 kHz to about 50 kHz; in otherembodiments greater than about 100 kHz and less than about 1 MHz; inother embodiments from about 500 kHz to about 15 MHz; and in yet otherembodiments greater than about 500 kHz and less than about 5 MHz. Theacoustic energy applied through the energy delivery member may be at agenerally high intensity of from about 1 mW/cm² to about 5 W/cm²; insome embodiments from about 50 mW/cm² to about 3 W/cm²; in otherembodiments from about 5-100 mW/cm²; in yet other embodiments from about0.1-1.5 W/cm². In other embodiments, the acoustic energy applied throughthe energy delivery member may be a generally high intensity ultrasoundof greater than about 1 W/cm² and less than about 25 kW/cm². In someembodiments, the acoustic energy applied through energy delivery memberhas an acoustic intensity from about 10 to about 1,000 W/cm²; in someembodiments from about 1,000 to about 15,000 W/cm²; and in yet otherembodiments from about 3,000 to about 10,000 W/cm². The generally highintensity ultrasound may be sufficient to ablate tissue and/or cellularstructures or debris, or it may be at a sub-ablation intensity that issufficient to disrupt tissue and/or cellular structures or debris butnot ablate. The pulse duration and repetition rate may be adjusted andmatched to the frequency and intensity of acoustic energy pulses toachieve the desired effect.

The high frequency acoustic energy may be selectably activated on acontinuous basis, or ultrasound energy may be applied, through theenergy delivery member, on an intermittent basis, and the frequencyand/or acoustic intensity may be adjustable and selectable by theoperator. Operation of the ultrasound transducer at duty cycles of lessthan about 80% is generally preferred; in some embodiments at dutycycles of less than 50%; and in yet other embodiments at duty cycles ofless than about 30%. Enhancement and/or coupling agents promoting and/ortargeting acoustic energy deposition may be used and may be provided toa target site through the insertion member and/or the energy deliverymember.

Handle 42, insertion wand 44 and energy delivery member 46, 48 may beprovided in an integrated, single piece construction, or they may beprovided as separate components that are detachable from one another.Handle 42 may be provided as a single- or multiple-use component.Insertion wands and/or energy delivery members may similarly be providedas integrated components or may be provided separately from one another,with appropriate interfaces for operation. Multiple configurations ofinsertion wands and/or energy delivery members may be provided foroperation on common or multiple handles, with appropriate insertionwands and/or energy delivery members being selectable by a userdepending on the circumstances of use. Insertion and energy deliverymembers may be provided as single- or multiple-use components, althoughthey may generally be provided as sterile, disposable components thatare mountable on a reusable handle. Device 40 may incorporate all of thecomponents required for operation, or it may interface with a separateconsole, or control unit (not shown), that provides electrical power,liquid for infusion or aerosol delivery, operating control features,displays, and the like.

In some embodiments, devices of the type illustrated in FIGS. 6 and 7are capable of selectively delivering high frequency acoustic energy, aliquid stream, aerosol particles and/or aerosol droplets, simultaneouslyor sequentially, in one or a plurality of delivery modes: continuousflow; intermittent flow; or high frequency pulsatile flow. Liquid,aerosol particles and/or aerosol droplets may be delivered from a commondischarge port sequentially and intermittently, or from multiple,dedicated discharge ports, simultaneously or sequentially, and on acontinuous or intermittent basis. Aspiration may be provided,additionally or alternatively, through one or more ports in theinsertion wand and/or energy delivery member. Insertion wand 24 may beprovided with one or more channels, or lumens, for delivery of liquids,aerosol particles, and/or aerosol droplets to a desired intranasal site,and for removal of material from the site by means of aspiration.

Controls may be provided on the device handle, as illustrated, or on anaccessory device or module, allowing a user to select acoustic frequencyand/or intensity, liquid and/or aerosol delivery modes, aspirationmodes, visualization modalities, or the like. Controls may also beprovided allowing a user to select from among various modes of operationor various pre-determined or pre-set operating modes. Devices of thepresent invention may thus be operated, manually or by selectableautomated operation, in a single mode or multiple modes.

In one embodiment, schematically illustrated in FIGS. 8A-8E, a device 40such as illustrated in and described with reference to FIGS. 6 and 7 maybe operated in a high frequency acoustic energy deposition mode in whichthe insertion wand 44 and energy delivery member 48 are positioned in anasal cavity, as shown in FIG. 8A. Energy delivery member 48 may beextended and guided, as shown in FIG. 8B, to contact mucus and/or debrisforming an obstruction within the osteomeatal complex in nasalpassageways. Acoustic energy delivery through delivery member 48 may beactivated at a preset or selectable acoustic energy frequency and/orintensity to heat and/or cavitate and/or ablate mucus and/or debrisforming the obstruction in the osteomeatal complex, as shownschematically in FIG. 8C. In another embodiment, the energy deliverymember may be positioned to contact tissue and activated at preset orselectable acoustic energy frequency and/or intensity levels to heatand/or cavitate and/or ablate selected tissue sites.

Delivery of the high frequency and/or high intensity acoustic energy maybe accompanied by infusion of liquids and/or aerosol particles ordroplets. Loosened and extraneous materials may be aspirated duringand/or following delivery of high frequency and/or high intensityacoustic energy and (optional) infusion of liquids and/or aerosolparticles, as shown schematically in FIG. 8D to remove obstructions andclear passageways, leaving cleared passageways as illustratedschematically in FIG. 8E. In another embodiment, therapeutic light, suchas ultraviolet light, may be emitted through a light transmissiveportion of the energy delivery member and/or an associated wand priorto, during and/or following delivery of acoustic energy.

Delivery of an implantable device such as a stent to passagewayspreviously cleared of obstructions using device 40, as schematicallyshown in FIGS. 8A-8E, may be desired to maintain the patency of clearedpassageways. FIGS. 8F-8H illustrate another embodiment in which animplantable device, such as a stent, may be deployed using a system ofthe present invention. FIG. 8F schematically shows a stent 50 in a smalldiameter delivery condition being deployed from a distal end ofinsertion member 44 over energy delivery member 48. In some embodiments,an implantable device may be deployed over or guided to a placement siteusing energy delivery member 48; in alternative embodiments, animplantable device may be deployed using an alternative guidance and/ordeployment system provided in connection with device 40. FIG. 8Gillustrates advancement of implantable stent 50 toward the desireddelivery site within the osteomeatal complex, still in the smalldiameter delivery condition, and FIG. 8H shows final placement of stent50, now expanded to the larger diameter final placement condition, inthe cleared passageway within the osteomeatal complex. Stents coated orotherwise associated with bio active materials for delivery of thebioactive materials to surrounding tissue sites may be placed usingsystems of the present invention.

FIGS. 9A-9D illustrate yet another device embodiment of the presentinvention, in which a deformable and expandable member, such as aninflatable chamber 52, may be deployed using a system of the presentinvention. In one embodiment, a flexible, deformable bladder orinflatable chamber is constructed from a material having high acousticaltransmission properties and is adapted for retaining an inflation mediumsuch as an acoustically transmissive material comprising a liquid orgel-like substance within its interior volume for delivery of acousticenergy to a target site. In another embodiment, the inflatable chamberis constructed from a material that is light (e.g., UV) transmissive andis adapted for retaining an inflation medium having high light (e.g.,UV) transmissive properties for delivery of light energy to the targetsite. In some embodiments, the inflatable chamber and the inflationmedium may have both light and acoustic energy transmissive propertiesfor delivery of both light energy and acoustic energy to the targetsite. In yet another embodiment, the inflatable chamber and/or theinflation medium may contain or be associated with one or more bioactivecompositions such as, but not limited to, antibiotics, cancertherapeutic compositions, steroid compositions, and the like. In thisembodiment, the bio active composition(s) may be provided as a coatingor may elute from the expandable member during use of the system.

The flexible, expandable chamber 52 may be stored in a collapsedcondition within wand 44 and may be deployed and expanded at a targetsite by introduction of the liquid or gel-like inflation medium, asshown schematically in FIGS. 9A-9D.

FIGS. 9A-9D illustrate deployment of expandable chamber 52 over energydelivery member 48, which also serves as a guide for deployment of theexpandable chamber. In alternative embodiments, an expandable chambermay be deployed using an alternative guidance and/or deployment systemprovided in connection with device 40. FIG. 9A schematically showsexpandable chamber 52 being deployed from a distal end of insertionmember 44 over energy delivery member 48. FIG. 9B schematically showsexpandable chamber 52 being further deployed and guided through aninternal passageway by energy delivery member 48. FIG. 9C schematicallyshows expandable chamber 52 in an exemplary fully deployed condition inwhich it encloses and extends beyond energy delivery member 48,substantially contacting the internal passageway walls and extendinginto a distal internal cavity. FIG. 9D schematically illustratesapplication of energy, such as ultrasound energy, through the inflationmedium, thereby providing delivery of energy, such as ultrasound energy,to tissues contacting the expandable chamber, and to neighboring tissuesas well. Energy delivery parameters and features as described above inconnection with the description of FIGS. 5A-5C are exemplary and may beused with the system and method embodiments described above.

In some embodiments, multiple pulsating liquid rinse and aerosoldelivery options, as well as multiple energy deposition options, may beprogrammed in the device, with various operating programs beingpredetermined and selectable by the user. In alternative embodiments, auser may select pulsating liquid rinse, aerosol delivery and/or energydeposition options by means of multiple selectable actuators. In any ofthese embodiments, multiple and selectable modes may be implemented,whereby programmed or selectable levels of liquid and/or aerosol flow orvolume, aerosol particle and/or droplet size, aerosol particle and/ordroplet density, pulsation frequency, temperature, acoustic energyfrequency, intensity, pulse repetition rate, duty cycle, and the like,may be selectable by the user.

Devices of the present invention may be provided as an integral unitthat may be used once or several times and then disposed of, or anintegral device may be reused on a frequent basis. Alternatively, asdescribed above, the handle and nostril interface member or deliverywand may be detachable from one another. In a multiple componentembodiment, the handle may be provided as a reusable component, whilethe detachable nostril interface member or delivery wand may be providedas a reusable or disposable element. Single or multiple use “covers” maybe provided for covering the nostril interface member or the deliverywand, providing replaceable sterile, or antiseptic surfaces forcontacting the nose and nasal passages. Such covers may be flexible andresilient and generally match the outer configuration of the nostrilinterface member and/or delivery wand, so that they may be mounted onand closely fitted over the interface member or delivery wand formultiple uses/multiple users, and the like.

Specific embodiments of methods and devices are described herein withreference to use in intranasal areas such as nasal passages, sinuses andsinus ostia and these methods and devices may be used, for example, fortreating common colds, nasal congestion and allergic rhinitis, as wellas sinusitis and other nasal conditions. They may be used for treatmentof acute or chronic conditions, and they may be used on a frequent basisto cleanse intranasal passages, thereby reducing bacterial infection andthe incidence of nasal congestion, colds, sinusitis and the like.

The methods and devices described herein are also suitable for treatingpathologies at other tissue sites that would benefit from biofilmdissolution, reduction in inflammation, reversal of mechanicalobstruction(s), reversal of hypertrophy, improvement of poorcirculation, repair of dysfunctional immune responses, repair ofdysfunctional immune modulation, removal of infection, and reversal ofdysfunctional cell proliferation, death or ablation. Methods and devicesof the present invention embodied in interventional catheter systemsmay, for example, be adapted for use in blood vessels, air passageways,the gastrointestinal tract, the genitourinary tract (e.g., urethra,bladder, ureters, renal calyxes, and the like) and other internalcavities and passageways.

In particular, methods and devices of the present invention as embodiedin interventional catheters may be used to deliver liquids to internalbody sites using a generally high frequency (sonic and/or ultrasonic)pulsatile flow. Interventional catheters of the present invention mayalso be adapted to deliver energy, such as acoustic and/or light energy,to tissue sites located in various parts of the body to address thefollowing exemplary pathologies:

pathologies of the cardiovascular system-such as atheroscerlosis,thromboses, ectopic cardiac pacing sites, valve lesions, cardiac musclelesions, aneurysms, intra-chamber emboli, intra-vascular emboli, and

pathologies of the gastrointestinal tract-such as obstructions, bezoars,strictures, cancers, hypertrophies, liver necrosis, liver masses,splenic abscesses, pancreatic tumors, pancreatic masses, pancreaticabscesses, and

pathologies of the genitourinary system-such as nephrolithiases,constrictures, fibroids, cervical cancer, abscesses, patent fallopiantubes, non-patent fallopian tubes, ovarian cysts, testicular masses,hydronephrosis, and

pathologies of the nervous system-such as brain abscesses, brain tumors,spinal cord abscesses, spinal cord tumors, dysfunctional nervetransmission, blood clots in and around the nerves, necrotic tissue inand around the nerves, and

pathologies of the musculoskeletal system-such as injured menisci,injured tendons and ligaments, degenerated intervertebral discs, chronicback pain (ablation of pain source nerves), infected joints, infectedbones, arthritic joints (removal of degenerated material andUS-stimulation of chondrocytes, poorly growing fractured bones (USstimulation of osteoblasts), and

pathologies of the dermatologic system-such as subcutaneous abscesses,chronic skin infections, eczema, chronic fungal infections (skin andnails).

FIGS. 10A-10C show highly schematic diagrams illustrating interventionalcatheter-based devices of the present invention. FIGS. 10A-C show acontroller 60 housing, or in operable communication with energy deliverysystems (such as acoustic and/or light-based energy delivery systems),liquid delivery systems, aspiration systems, and the like, and havingexemplary selectable control operators 61A, 61B and 61C for operatingenergy delivery systems, liquid delivery systems, aspiration systems,etc. Suitable systems, control features and selectable control operatorsare well known in the art and are not described in detail herein.

FIGS. 10A-10C each illustrate a catheter 62 exiting controller 60 at aproximal end and having an operating head 64, 66, 68 located at or neara distal end of the catheter. The catheter may be adapted forintroduction to and guidance through various types of body lumens andpassageways; many catheter systems are known in the art and are suitablefor use in different body lumens and passageways. Catheter-based systemsof the present invention may be designed for use with or without a guidewire or another guidance system, and may be guided using remotelyoperated (e.g., robotic) guidance systems.

FIG. 10A schematically shows an operating head 64 of the type shown anddescribed above with reference to FIG. 3. Operating head 64 may beemployed for delivery of a liquid or aerosol stream from one or moredischarge ports(s) at one or more to pulsatile frequencies and/orenergies, as described above. Operating head 64 may also incorporate anenergy delivery member for delivering generally high frequency and/orhigh intensity ultrasound energy, alone or in combination with anothertreatment modality such as administration of an antimicrobial ortherapeutic agent, application of electromagnetic radiation (e.g., UVlight), an electrical field, radio frequency energy, laser energy,microwave energy, or the like.

FIG. 10B schematically shows an operating head 66 of the type shown inFIGS. 5A-5C. This operating head may perform any of the functionsdescribed with reference to operating head 64, described above, and mayadditionally comprise an energy delivery member in the form of acontrollably expandable chamber for contacting tissue in oddly shapedand unevenly contoured cavities and passageways. The expandable chambermay be filled with an energy transmissive material, such as anacoustically and/or light transmissive material, for delivery ofacoustic energy and/or light energy to tissue surfaces forming cavityand passageway walls, as described above. The expandable chamber mayalso be employed for delivery of a bioactive composition, such as a drugor another agent, prior to, during or following deployment of theexpandable chamber, also as described above.

FIG. 10C schematically shows an operating head 68 of the type shown inFIGS. 7, 8A-8D, 8F-8H, and 9-9D. This operating head may perform any ofthe functions described with reference to operating heads 64 and 66,described above, and is additionally provided with an acoustic energydelivery member that is extendible and retractable to deliver energy,such as acoustic and/or light energy, to an internal target site.Operating head 64 may also incorporate an energy delivery member fordelivering generally high frequency and/or high intensity ultrasoundenergy, alone or in combination with another treatment modality such asadministration of an antimicrobial or therapeutic agent, application ofelectromagnetic radiation (e.g., UV light), an electrical field, radiofrequency energy, laser energy, microwave energy, or the like.

It will be appreciated that the methods and systems of the presentinvention may be embodied in a variety of different forms, and that thespecific embodiments shown in the figures and described herein arepresented with the understanding that the present disclosure isconsidered exemplary of the principles of the invention, and is notintended to limit the invention to the illustrations and descriptionprovided herein. Accordingly, the descriptions provided above areconsidered as being illustrative and exemplary of specific structures,aspects and features within the broad scope of the present invention andnot as limiting the scope of the invention.

1. A method for treating a target site at a tissue, wherein the targetsite comprises a tissue surface, a body cavity or obstruction,comprising delivering at least one of fluids and aerosols to the targetsite using a pulsatile flow characterized by pulsations having afrequency of greater than 1500 Hz.
 2. The method of claim 1, wherein thefrequency of pulsations is in the ultrasound frequency range.
 3. Themethod of claim 1, comprising delivering an aerosol to the target siteusing a pulsatile flow having a frequency of greater than 1500 Hz and apressure of more than about 10 mmHg and less than about 160 mmHg.
 4. Themethod of claim 1, wherein the pulsatile flow is characterized bypulsations having at least two different frequencies.
 5. The method ofclaim 4, wherein the at least two different frequencies include afrequency in a sub-ultrasound frequency range and a frequency in theultrasound frequency range.
 6. The method of claim 1, comprisingdelivering at least one of fluids and aerosols using pulsatile flowscharacterized by multiple modes of administration, with each mode ofadministration being characterized by pulsations having a differentfrequency, intensity, pulse duration, pulse repetition rate and/or dutycycle.
 7. The method of claim 1, additionally comprising delivering atleast one additional treatment modality in combination with the deliveryof at least one of fluids and aerosols, wherein the additional treatmentmodality includes administration of an antimicrobial or therapeuticagent, application of electromagnetic radiation, application of anelectrical field, application of radio frequency energy, application oflight energy, and/or application of microwave energy.
 8. The method ofclaim 1, additionally comprising delivering high frequency acousticenergy to the target site in combination with the delivery of at leastone of fluids and aerosols.
 9. The method of claim 1, wherein the fluidor the aerosol comprises at least one of the following components:saline, an antibiotic agent, a drug, hypertonic saline, lactatedringer's solution, dead sea salt solution, antibiotics, midazolam,fentanyl, insulin, growth hormone, one or more growth factors,gentamycin, clindamycin, ciprofloxacin, cefuroxime, cancer treatmentcompositions, such as a cancer chemotherapeutic agent, levofloxocin,tobramycin, ampicillin+sulbactam, amphotericin, tobramycin/amphotericincombinations, cefotaxime, ceftriaxone, fluticasone, budesonide,synthetic antimicrobial molecules such as agangiocides, mometasonefuroate monohydrate, xylitol, eucalyptus, tea tree oil, capsaicin,grapefruit seed extract and oil of wintergreen.
 10. The method of claim1, additionally comprising aspirating material from the target siteduring and/or following delivery of the fluid and/or aerosol.
 11. Asystem for delivery of at least one of fluids and aerosols to a tissuesurface, cavity or obstruction, comprising a handheld device having ahandle and at least one fluid and/or aerosol discharge port, wherein thehandheld device is adapted to deliver a pulsatile flow of fluids and/oraerosols at a pulsation frequency of greater than 1500 Hz.
 12. Thesystem of claim 11, wherein the handheld device is adapted to deliver apulsatile flow of fluids and/or aerosols at a pulsation frequency ofgreater than 1500 Hz and at a pressure of more than about 10 mmHg andless than about 160 mmHg.
 13. The system of claim 11, wherein thehandheld device is adapted to deliver a pulsatile flow of fluids and/oraerosols at alternating pulsation frequencies corresponding tofrequencies that promote entry of the fluid and/or aerosol into a tissuesurface, cavity or obstruction; reduce biofilms; degrade pathologicaltissue; improve circulation; and/or modulate local immune responses. 14.The system of claim 11, wherein the handheld device additionallycomprises at least one aspiration port.
 15. The system of claim 14,additionally comprising a system for collection of material removed byaspiration.
 16. The system of claim 11, wherein the handheld device isadapted to provide programmed or selectable levels of at least one ofthe following parameters: liquid and/or aerosol flow; liquid and/oraerosol volume, aerosol particle and/or droplet size; aerosol particleand/or droplet density; pulsation frequency; and temperature.
 17. Amethod of delivering a composition to a body site, comprising: providingthe composition in at least one of a fluid and aerosol form; generatingpulsations of at least one of the fluid and aerosol forms at two or morefrequencies; and delivering the pulsations to the body site at the twoor more frequencies.
 18. The method of claim 17, comprising providingthe composition in an aerosol form and delivering the pulsations to thebody site at two or more frequencies in the sub-ultrasound frequencyrange.
 19. The method of claim 17, comprising providing the compositionin an aerosol form and delivering the pulsations to the body site at twoor more frequencies, wherein at least one of the frequencies is in theultrasound frequency range.
 20. The method of claim 17, wherein at leastone of the two or more frequencies correlates with acoustic propertiesof at least one of the following pathologic processes: biofilm;inflammation; mechanical obstruction; hypertrophy, poor circulation,dysfunctional immune response; dysfunctional immune modulation,infection; and dysfunctional cell proliferation or death.